Reduction of infection associated with medical device

ABSTRACT

Anti-infective articles capable of preventing infection associated with implantation of medical devices include low levels of anti-infective agents, may cover only a fraction of the portion of the medical device and be effective, or may rapidly elute anti-infective agent, without sustained elution, and still be effective.

RELATED APPLICATION

This application claims the benefit of the filing date of provisionalU.S. Application Ser. No. 61/106,254 filed Oct. 17, 2008, andprovisional U.S. Application Ser. No. 61/113,370 filed Nov. 11, 2008.

FIELD

This disclosure relates, inter alia, to implantable medical devices.More particularly, it relates to systems, devices and methods forpreventing infection associated with implantation of implantable medicaldevices.

BACKGROUND

A wide variety of implantable medical devices (IMDs) are commerciallyavailable for clinical implantation, including cardiac pacemakers,cardioverter/defibrillators having pacing capabilities, other electricalstimulators including spinal cord, deep brain, nerve, and musclestimulators, drug delivery systems, cardiac and other physiologicmonitors, cochlear implants, etc. Such IMDs often contain a batterypowered component that is implanted subcutaneously at a surgicallyprepared site, referred to as a “pocket”. Associated devices, such asmedical leads and catheters, extend from the subcutaneous site to othersubcutaneous sites or deeper into the body to organs or otherimplantation sites.

The surgical preparation and initial or replacement IMD implantationsare conducted in a sterile field, and the IMD components are packaged insterile containers or sterilized prior to introduction into the sterilefield. However, despite these precautions, there always is a risk ofintroduction of microbes into the pocket. Surgeons therefore typicallyapply disinfectant or antiseptic agents to the skin at the surgical siteprior to surgery, directly to the site before the incision is closed,and prescribe oral antibiotics for the patient to ingest duringrecovery.

Despite these precautions, infections do occur. In addition, once thepocket becomes infected, the infection can migrate along the lead orcatheter to the heart, brain, spinal canal or other location in whichthe lead or catheter is implanted. Such a migrating infection can becomeintractable and life-threatening, requiring removal of the IMD in thepocket and associated devices, such as leads and catheters. Removal of achronically implanted lead or catheter can be difficult and dangerous.Aggressive systemic drug treatment is also provided to treat theinfection.

Impregnating, coating or otherwise disposing one or more anti-infectiveagent in, on or about an IMD has been proposed. Some such IMDs arecurrently commercially available. However, the use of anti-infectiveagents with permanently or temporarily implantable IMDs raises concernssuch as development of strains of microbes resistant to theanti-infective agents and the development of allergic reactions to theanti-infective agents associated with the IMD. The presence of lowlevels of anti-infective agents over time raises concerns regarding thedevelopment of resistant strains of microbes, and large amounts or thepresence of anti-infective agent over time raises concerns regardingdevelopment of an allergic reaction.

SUMMARY

The present disclosure describes, inter alia, systems, devices andmethods that can be used to prevent infection associated withimplantation of medical devices. The use of low levels of anti-infectiveagents has been shown to be effective in preventing such infection. Inaddition, it has been shown that anti-infective agents that are notplaced over a large portion of an implantable medical device are stilleffective at preventing infection around the entire device followingimplantation. Further, it has been unexpectedly shown that rapid elutionof anti-infective agent from a polymeric matrix, without sustainedelution, is sufficient to prevent infection. Systems and methods thatemploy low levels of anti-infective agents or rapidly elutinganti-infective articles should reduce the likelihood of development ofresistant strains of microbes and development of an allergic reaction.

In various embodiments, the invention provides an implantable medicalsystem. The system includes an implantable medical device having (i) anexterior surface having a surface area, and (ii) an article configuredto contact the exterior surface. The article includes minocycline in anamount of between 1 and 500 micrograms per square inch of the exteriorsurface area of the device and rifampin in an amount between 1 and 500micrograms per square inch of the exterior surface area of the device.In various embodiments, minocycline is present in the article in anamount between 1 and 100 micrograms (e.g, between 3 and 50 micrograms orbetween 5 and 25 micrograms) per square inch of the exterior surfacearea of the device and wherein rifampin is present in the article in anamount between 1 and 100 micrograms (e.g, between 3 and 50 micrograms orbetween 5 and 25 micrograms) per square inch of the exterior surfacearea of the device. In various embodiments, the article includes apolymeric material, such as silicone, and may be formed substantiallyfrom a polymeric material. In various embodiments, the article has anaverage thickness of 0.01 inches or less (e.g., 0.0075 inches or less or0.005 inches or less). In various embodiments, the article has first andsecond major surfaces, with the first major surface being in contactwith the device and the second major surface having a surface area of30% or less than the exterior surface area of the device.

In various embodiments, the invention provides an implantable medicalsystem. The system includes an implantable medical device having (i) anexterior surface having a surface area, and (ii) an article configuredto contact the exterior surface. The article has an average thickness0.01 inches or less and contains an effective amount of one or moreanti-infective agents, such as minocycline and rifampin. In variousembodiments, the article has an average thickness of 0.0075 inches orless or 0.005 inches or less. In various embodiments, minocycline ispresent in the article in an amount of between 1 and 1500 micrograms(e.g., between 3 and 750 micrograms or between 5 and 400 micrograms) persquare inch of the exterior surface area of the device, and rifampin ispresent in the device in an amount of between 1 and 1500 micrograms(e.g., between 3 and 750 micrograms or between 5 and 400 micrograms) persquare inch of the exterior surface area of the device.

In various embodiments, the invention provides an implantable medicalsystem. The system includes an implantable medical device having (i) anexterior surface having a surface area, and (ii) an article configuredto contact with the exterior surface area. The article has first andsecond major surfaces. The second major surface has a surface area of30% or less (e.g., 20% or less, 10% or less, or 5% or less) than theexterior surface area of the device. The article contains an effectiveamount of one or more anti-infective agents, such as minocycline andrifampin.

In various embodiments, the invention provides an implantable medicalsystem. The system includes (i) an implantable medical device having anexterior surface having a surface area, and (ii) an article configuredto contact the exterior surface. The article contains an anti-infectiveagent in an amount per square inch of the exterior surface area of thedevice. The amount of the anti-infective agent is: (the minimuminhibitor concentration against a strain of S. aureus in an amount permilliliter) times (one milliliter) times (a number between the range of1,500 and 50,000).

In various embodiments, the invention provides an implantable medicalsystem. The system includes an implantable medical device having (i) anexterior surface having a surface area, and (ii) an article configure tocontact the exterior surface. The article includes an effective amountof one or more anti-infective agents, such as minocycline and rifampin.The article is configured to elute 40% or more of the anti-infectiveagents within 48 hours of being implanted in a patient. In variousembodiments, the article is configured to elute 60% or more of theanti-infective agent within 24 hours of being implanted in a patient. Invarious embodiments, the article is configured to release substantiallyall the anti-infective agent with 24 hours. In various embodiments, thearticle is configured to release substantially all the anti-infectiveagent with 72 hours. In various embodiments, the anti-infective agentincludes minocycline and the article is configured to releasesubstantially all the minocycline within 24 hours of being implanted. Invarious embodiments, the anti-infective agent includes rifampin and thearticle is configured to release substantially all the rifampin within72 hours of being implanted.

In various embodiments, the invention provides an implantable medicalsystem. The system includes an implantable medical device having (i) anexterior surface having a surface area, and (ii) an article configuredto contact the exterior surface area. The article includes (i)minocycline in an amount of between 100 and 2000 and (ii) rifampin in anamount between 1000 and 2000 micrograms. In various embodiments, thearticle has an average thickness of 0.01 inches or less (e.g., 0.0075inches or less or 0.005 inches or less).

In various embodiments, the invention provides a method for preventinginfection in proximity to an implanted medical device. The methodincludes implanting, in proximity to the implanted device, an articlecontaining an anti-infective agent in a patient. The article has firstand second opposing major surfaces. The surface area of the secondsurface of the article is 30% or less than an exterior surface area ofthe implantable medical device. The method further includes eluting theanti-infective agent from the article to prevent an infection fromforming in proximity to the implanted device. In various embodiments,implanting the article includes implanting the device, with which thearticle is in contact. In various embodiments, eluting theanti-infective agent from the article includes eluting 60% or more ofthe anti-infective agent within 24 hours of implanting the article.

In various embodiments, the invention provides a method for preventinginfection in proximity to an implanted medical device. The methodincludes implanting, in proximity to the implanted device, an articlecontaining an anti-infective agent in a patient. The article has anaverage thickness 0.01 inches or less. The method further includeseluting the anti-infective agent from the article to prevent aninfection from developing in proximity to the implanted device. Invarious embodiments, implanting the article includes implanting thedevice, with which the article is in contact. In various embodiments,eluting the anti-infective agent from the article includes eluting 60%or more of the anti-infective agent within 24 hours of implanting thearticle.

In various embodiments, the invention provides a method for preventinginfection in proximity to an implanted medical device. The methodincludes implanting, in proximity to the implanted device, an articlecontaining an anti-infective agent in an amount per square inch of theexterior surface area of the device. The amount of the anti-infectiveagent is: (the minimum inhibitor concentration against a strain of S.aureus in an amount per milliliter) times (one milliliter) times (anumber between the range of 1,500 and 50,000). The method furtherincludes eluting the anti-infective agent from the article to prevent aninfection from forming in proximity to the implanted device. In variousembodiments, implanting the article includes implanting the device, withwhich the article is in contact. In various embodiments, eluting theanti-infective agent from the article includes eluting 60% or more ofthe anti-infective agent within 24 hours of implanting the article.

In various embodiments, the invention provides a method for preventinginfection in proximity to an implanted medical device. The methodincludes implanting, in proximity to the implanted device, an articlecomprising (i) minocycline in an amount of between 1 and 500 microgramsper square inch of the exterior surface area of the device and (ii)rifampin in an amount between 1 and 500 micrograms per square inch ofthe exterior surface area of the device. The method further includeseluting the anti-infective agent from the article to prevent aninfection from forming in proximity to the implanted device. In variousembodiments, implanting the article includes implanting the device, withwhich the article is in contact. In various embodiments, eluting theanti-infective agent from the article includes eluting 60% or more ofthe anti-infective agent within 24 hours of implanting the article.

In various embodiments, the invention provides a method for preventinginfection in proximity to an implanted medical device. The methodincludes implanting, in proximity to the implanted device, ananti-infective article having (i) minocycline in an amount of between100 and 2000 and (ii) rifampin in an amount between 100 and 2000micrograms. The method further includes eluting the minocycline andrifampin from the article to prevent an infection from forming inproximity to the implanted device. In various embodiments, implantingthe article includes implanting the device, with which the article is incontact. In various embodiments, eluting the anti-infective agent fromthe article includes eluting 60% or more of the anti-infective agentwithin 24 hours of implanting the article.

In various embodiments, the invention provides a method for preventinginfection in proximity to an implanted medical device. The methodincludes implanting, in proximity to the implanted device, ananti-infective article containing effective amounts of minocycline andrifampin. The method further includes eluting the minocycline andrifampin from the article to prevent an infection from forming inproximity to the implanted device such that at five days followingimplantation 300 micrograms or less of the minocycline or rifampinremain in the article.

In various embodiments, the invention provides kits containing thecomponents of the systems or methods described above or the articles inthe systems or methods described above.

By providing devices, systems and methods that incorporate lower levelsof anti-infective agents or that rapidly elute anti-infective agentsconcerns associated with development of antibiotic resistance or andallergic reaction can be minimized. These and other advantages will bereadily understood from the following detailed descriptions when read inconjunction with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a diagrammatic representation of a representative environmentof a system implanted in a patient.

FIGS. 2A-D are diagrammatic representations of side views ofrepresentative anti-infective articles.

FIG. 3 is a diagrammatic representation of a perspective view of arepresentative article having a thickness.

FIG. 4A-C are diagrammatic representations of side views ofrepresentative anti-infective articles associated with a representativeimplantable device.

FIG. 5 is a graph showing the elution profile of minocycline out of thinsilicone anti-infective articles.

FIG. 6 is a graph showing the elution profile of rifampin out of thinsilicone anti-infective articles.

FIG. 7 is a showing the elution profile of minocycline out of thinsilicone anti-infective articles.

FIG. 8 is a graph showing the elution profile of rifampin out of thinsilicone anti-infective articles.

FIG. 9 is a summary of results testing the efficacy, drug content anddrug elution of various anti-infective articles.

The drawings are not necessarily to scale. Like numbers used in thefigures refer to like components, steps and the like. However, it willbe understood that the use of a number to refer to a component in agiven figure is not intended to limit the component in another figurelabeled with the same number.

DETAILED DESCRIPTION

In the following detailed description, reference is made to theaccompanying drawings that form a part hereof, and in which are shown byway of illustration several specific embodiments of devices, systems andmethods. It is to be understood that other embodiments are contemplatedand may be made without departing from the scope or spirit of thepresent invention. The following detailed description, therefore, is notto be taken in a limiting sense.

All scientific and technical terms used herein have meanings commonlyused in the art unless otherwise specified. The definitions providedherein are to facilitate understanding of certain terms used frequentlyherein and are not meant to limit the scope of the present disclosure.

As used herein, an “effective amount” of an anti-infective agent is anamount that prevents, reduces the severity of, or delays an infection.

As used in this specification and the appended claims, the singularforms “a”, “an”, and “the” encompass embodiments having pluralreferents, unless the content clearly dictates otherwise. As used inthis specification and the appended claims, the term “or” is generallyemployed in its sense including “and/or” unless the content clearlydictates otherwise.

Unless otherwise indicated, all numbers expressing feature sizes,amounts, and physical properties used in the specification and claimsare to be understood as being modified in all instances by the term“about.” Accordingly, unless indicated to the contrary, the numericalparameters set forth in the foregoing specification and attached claimsare approximations that can vary depending upon the desired propertiessought to be obtained by those skilled in the art utilizing theteachings disclosed herein.

The recitation of numerical ranges by endpoints includes all numberssubsumed within that range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3,3.80, 4, and 5) and any range within that range.

The present disclosure describes, inter alia, systems, devices andmethods that can be used to prevent infection associated withimplantation of medical devices. In various embodiments, methods,systems and devices that use of low levels of anti-infective agents,that rapidly elute anti-infective agent, e.g., from a polymeric matrix,or that employ anti-infective articles that cover only a portion of, orare only a fraction of the surface area of, an implantable device aredescribed.

Referring to FIG. 1, a general environment of an implantable device 50implanted in a patient is shown. In the embodiment depicted in FIG. 1,device 50 is a ventricular pacemaker, but it will be understood that theteachings of provided herein may be applied with regard to anyimplantable medical device, such as a defibrillator, an infusion device,a neurostimulator, a monitoring device, a cochlear implant, a medicallead, a medical catheter, or the like. As shown in FIG. 1, device 50 isimplanted in a subcutaneous pocket 140 of a patient 10. Device 50 asshown is implanted pectorally, but it will be understood that device maybe implanted at any medically acceptable location of patient 10,including in the abdomen. An anti-infective article 15 is shown as beingdisposed about device 50, but may be disposed on or generally located inproximity to device 50. Article 15 as depicted includes a side opening35,infective exposing a portion of housing 55 of device 50. Article 15as depicted also includes an edge opening 40 allowing for a connectorblock 60 of device 50 to be exposed to facilitate connection of anassociated device 70 to device 50. Associated device 70 shown in theembodiment depicted in FIG. 1 is a lead, but may be any suitable devicesuch as a lead or catheter, as appropriate.

In general, any suitable anti-infective agent may be used in associationwith an anti-infective article. For example, one or more antibioticsuitable for use in a human may be employed in accordance with variousembodiments presented herein. The antibacterial agent may havebateriostatic or bacteriocidal activities. Nonlimiting examples ofclasses of antibiotics that may be used include tetracyclines (e.g.,minocycline), rifamycins (e.g., rifampin), macrolides (e.g.,erythromycin), penicillins (e.g., nafcillin), cephalosporins (e.g.,cefazolin), other beta-lactam antibiotics (e.g., imipenem, aztreonam),aminoglycosides (e.g., gentamicin), chloramphenicol, sufonamides (e.g.,sulfamethoxazole), glycopeptides (e.g., vancomycin), quinolones (e.g.,ciprofloxacin), fusidic acid, trimethoprim, metronidazole, clindamycin,mupirocin, polyenes (e.g., amphotericin B), azoles (e.g., fluconazole)and beta-lactam inhibitors (e.g., sulbactam). Nonlimiting examples ofspecific antibiotics that may be used include minocycline, rifampin,erythromycin, nafcillin, cefazolin, imipenem, aztreonam, gentamicin,sulfamethoxazole, vancomycin, ciprofloxacin, trimethoprim,metronidazole, clindamycin, teicoplanin, mupirocin, azithromycin,clarithromycin, ofloxacin, lomefloxacin, norfloxacin, nalidixic acid,sparfloxacin, pefloxacin, amifloxacin, enoxacin, fleroxacin,temafloxacin, tosufloxacin, clinafloxacin, sulbactam, clavulanic acid,amphotericin B, fluconazole, itraconazole, ketoconazole, and nystatin.One of ordinary skill in the art will recognize that other antibioticsmay readily be used.

It is desirable that the antibiotic(s) selected kill or inhibit thegrowth of one or more bacteria that are associated with infectionfollowing surgical implantation of a medical device. Such bacteria arerecognized by those of ordinary skill in the art and includeStapholcoccus aureus and Staphlococcus epidermis. To enhance thelikelihood that bacteria will be killed or inhibited, it may bedesirable to combine one or more antibiotic. It will be recognized byone of ordinary skill in the art that antimicrobial agents havingdifferent mechanisms of action or different spectrums of action may bemost effective in achieving such an effect. In particular embodiments,rifampin and micocycline are used in combination.

Referring to FIG. 2, diagrammatic illustrations of side views ofrepresentative anti-infective articles 15 are shown. Article 15 may beany suitable shape and may take any suitable form. For example, article15 may be in the form of a tube, sheath, sleeve, boot, disc, or thelike. Article 15 may be formed from polymeric material and may beextruded, molded, or otherwise formed. Examples of commonly usedsuitable polymeric materials include organic polymers such as silicones,polyamines, polystyrene, polyurethane, acrylates, polysilanes,polysulfone, methoxysilanes, and the like. Other polymers that may beutilized include polyolefins, polyisobutylene and ethylene-alphaolefincopolymers; acrylic polymers and copolymers, ethylene-covinylacetate,polybutylmethacrylate; vinyl halide polymers and copolymers, such aspolyvinyl chloride; polyvinyl ethers, such as polyvinyl methyl ether;polyvinylidene halides, such as polyvinylidene fluoride andpolyvinylidene chloride; polyacrylonitrile, polyvinyl ketones; polyvinylaromatics, such as polystyrene, polyvinyl esters, such as polyvinylacetate; copolymers of vinyl monomers with each other and olefins, suchas ethylene-methyl methacrylate copolymers, acrylonitrile-styrenecopolymers, ABS resins, and ethylene-vinyl acetate copolymers;polyamides, such as Nylon 66 and polycaprolactam; polycarbonates;polyoxymethylenes; polyimides; polyethers; epoxy resins; polyurethanes;rayon; rayon-triacetate; cellulose; cellulose acetate, cellulosebutyrate; cellulose acetate butyrate; cellophane; cellulose nitrate;cellulose propionate; cellulose ethers; carboxymethyl cellulose;polyphenyleneoxide; and polytetrafluoroethylene (PTFE).

Article 15 may comprise a biodegradable polymeric material, such assynthetic or natural bioabsorbable polymers. Synthetic bioabsorbablepolymeric materials that can be used to form the coating layers includepoly(L-lactic acid), polycaprolactone, poly(lactide-co-glycolide),poly(ethylene-vinyl acetate), poly(hydroxybutyrate-covalerate),polydioxanone, polyorthoester, polyanhydride, poly(glycolic acid),poly(D,L-lactic acid), poly(glycolic acid-co-trimethylene carbonate),polyphosphoester, polyphosphoester urethane, poly(amino acids),cyanoacrylates, poly(trimethylene carbonate), poly(iminocarbonate),copoly(ether-esters) such as PEO/PLA, polyalkylene oxalates,polyphosphazenes, and polyarylates including tyrosine-derivedpolyarylates. According to another exemplary embodiment, the polymericmaterials can be natural bioabsorbable polymers such as, but not limitedto, fibrin, fibrinogen, cellulose, starch, collagen, and hyaluronicacid. “Biodegradable”, “bioerodable”, and “bioabsorbable” are usedherein interchangeably.

As shown in FIG. 2A-C, article 15 may be in the form of a boot designedto be placed around device 50. Boot 15 may contain an edge opening 40 toallow for connection of an associated device 70. Boot 15 may (FIGS.2B-C) or may not (FIG. 2A) include one or more side hole 35, which maybe of any suitable size. As shown in FIG. 2D, article 15 may in the formof a disc.

As shown in FIG. 3, article 15 has first 200 and second 210 opposingmajor surfaces, and a thickness. In various embodiments, the article 15has an average thickness of 0.01 inches (0.026 cm) or less. For example,article 15 may have an average thickness of 0.0075 inches (0.019 cm) orless or 0.005 inches (0.013 cm). In various embodiments, article 15 hasan average thickness that allows for 60% or more (e.g., 70% or more, 80%or more, etc.) of anti-infective agent associated with the article toelute within 24 hours of being implanted in a patient. In someembodiments, substantially all of the antimicrobial agent is elutedwithin 72 hours. In some embodiments, substantially all of theantimicrobial agent is eluted within 24 hours.

Article 15 is placed generally in proximity to device 50 in use. Forexample, article 15 may be placed in subcutaneous pocket 140 or may beplaced on or about device 50. In various embodiments, article 15 isbonded, adhered to, coated on, or otherwise attached to housing 55.Referring to FIG. 4, various locations of article 15 relative to device50 are shown. The article 15 shown in FIG. 4 is a disc, but it will beunderstood that the discussion that follows will be applicableregardless of shape or form of article 15. Whether or not bonded,adhered, or coated on device 50, article 15 may be generally centered ona side of housing 55 (FIG. 4A), placed on or over a portion of connectorblock 60 (FIG. 4B), or otherwise located in proximity to device 50 (FIG.4C).

As shown in FIG. 4, first major surface 200 of article 15 may be incontact with device 50 and second major surface 210 may be facing awayfrom the external surface of device 50. Surprisingly and as shown in theExample that follows, the surface area of the second major surface 210of article 15 may be only a small percentage of the external surfacearea of device 50 to effectively prevent infection. In variousembodiments, the surface area of the second major surface 210 is 30% orless, 20% or less, 10% or less, or 5% or less than the external surfacearea of device 50. As used herein, “surface area” is calculated on amacroscopic scale. For example, a smooth surface will be considered tohave the same surface area as a rough or porous surface. One suitableway of calculating the relative surface area of the second major surface210 of article 15 to the external surface area of device 50 is todetermine the percentage of the external surface of device 50 that thesecond major surface 210 of article 15 covers when in contact withdevice 50.

An anti-infective agent may be present in an eluting article at anysuitable concentration. For example, an anti-infective agent maycomprise 0.1% to 50%, 0.1% to 20%, 0.1% to 5%, 1% to 10%, etc. of theweight of the article. In various embodiments, one or moreanti-infective agent may be present in the article in an amount of 0.25to 1% by weight of the article. Anti-infective agent may be incorporatedinto an article in a variety of ways. For example, anti-infective agentcan be covalently grafted to a polymer of the article 15, either aloneor with a surface graft polymer. Alternatively, anti-infective agent maybe coated onto the surface of the article 15 either alone or intermixedwith an overcoating polymer. Anti-infective agent may be physicallyblended with a polymer of an article 15 as in a solid-solid solution.Anti-infective agent may be impregnated into a polymer of an article 15by swelling the polymer in a solution of the appropriate solvent. Anymeans of incorporating anti-infective agent into or on an article 15 maybe used, provided that anti-infective agent may be released, leached ordiffuse from article 15 on or after contact with bodily fluid or tissue.Regardless of how an anti-infective agent or agents are associated witharticle 15, it is desirable that agent or agents are incorporated in anamount effective to prevent, reduce the severity, or delay an infection.

For example, it has been surprisingly shown (see Example below) thatarticles 15 including as low as about 150-200 micrograms of minocyclineand 150-200 micrograms of rifampin were able to successfully preventinfection in proximity to a device 50 implanted in a subcutaneous pocket140. In various embodiments, between about 100-2000 micrograms ofrifampin and between about 100-2000 micrograms of minocycline are loadedinto, mixed with, or otherwise associated with article 50.

In various embodiments, at least 200 micrograms of minocycline andrifampin are capable of being eluted from article 15 in a 24 hour timeperiod between six and seven days, between five and six days, betweenfour and five days, between three and four days, between two and threedays, between one and two days, or within one day followingimplantation. Alternatively, or in addition, article 15 may contain 300micrograms or less of minocycline or rifampin seven, six, five, four,three, two, or one day following implantation.

Another way to express effective amounts of anti-infective agents is perexternal surface area of device 50. For example, in various embodiments,between 1 and 500 micrograms (e.g., between 1 and 100 micrograms,between 3 and 50 micrograms or between 5 and 25 micrograms) ofminocycline per square inch of the external surface area of device 50and between 1 and 500 micrograms (e.g., between 1 and 100 micrograms,between 3 and 50 micrograms or between 5 and 25 micrograms) of rifampinper square inch of the external surface area of device 50 are used toprevent, reduce severity, or delay onset of an infection. In variousembodiments, one or more anti-infective agent is associated with article15 such that an amount of the anti-infective agent is present perexternal surface area of device 50. One way to determine a suitableamount of the anti-infective agent is to multiply the minimum inhibitoryconcentration (MIC) of the anti-infective agent against a strain of S.aureus in an amount per milliliter by the product of one millilitertimes a number between the range of 1,500 and 50,000; i.e., (MIC) times(1 ml) times (between 1,500 and 50,000).

Articles 15 may comprise polymeric materials designed to control therate at which an anti-infective agent is released, leached, or diffusedfrom the polymeric material. As used herein, “release”, “leach”,“diffuse”, “elute” and the like are used interchangeably when referringto an anti-infective agent with respect to an article serving as avehicle for delivering the anti-infective agent. Any known or developedtechnology may be used to control the release rate. For example, acoating layer may be designed according to the teachings of WO/04026361,entitled “Controllable Drug Releasing Gradient Coating for MedicalDevices.” Porosity of article may also affect release rate of ananti-infective agent, once implanted. Porous materials known in the artinclude those disclosed in U.S. Pat. No. 5,609,629 (Fearnot et al.) andU.S. Pat. No. 5,591,227 (Dinh et al.). Typically polymers arenon-porous. However, non-porous polymers may be made porous throughknown or developed techniques, such as extruding with CO₂ or by foamingthe polymeric material prior to extrusion or coating. By way of anotherexample, the thickness of the article may have effects on the releaserate.

As shown in the Example that follows, it has been surprisingly shownthat an article 15 that releases a substantial amount of anti-infectiveagent in a short period of time, as opposed to sustained long durationrelease, is effective at preventing infection associated withimplantation of device 50. In various embodiments, article 15 isconfigured to elute 60% or more (e.g., 70% or more, 80% or more, etc.)of anti-infective agent associated with the article within 24 hours ofbeing implanted in a patient 10. In some embodiments, substantially allof the antimicrobial agent is eluted within 72 hours. In someembodiments, substantially all of the antimicrobial agent is elutedwithin 24 hours.

In various embodiments, article 15 is configured to elute 40% or more ofanti-infective agent associated with the article within 48 hours ofbeing implanted in a patient 10. In some embodiments, substantially allof the antimicrobial agent is eluted within one week.

Example

Silicone boots and discs loaded with minocycline and rifampin wereplaced about or in contact with an implantable pulse generator andimplanted into rabbits along with an inoculum of S. aureus to determinewhether such boots or discs would prevent an infection from developing.

I. Methods

A. Boot and Disc Preparation

Silicone boots for disposing about Restore® implantable neurostimulators(Medtronic, Inc.) and having a thickness of 0.015 inches (“thick”) or0.005 inches (“thin”) were formed from LSR (Dow Corning 4850) or ETR(Dow Corning 4735) by molding or dip covering. 1.25 inch diameter discswere punched from the boot to create side holes on either side of theboot. The punched discs were sutured to Restore® implantableneurostimulators and were also evaluated for their ability to preventinfection from forming

B. Drug Loading

Minocycline and rifampin were incorporated into the boots, with orwithout side holes, and discs as follows. Silicone material waspre-extracted with butyl acetate to remove non-cross-linked polymer.After drying, the pre-extracted silicone was treated in aminocycline/rifampin solution prepared by dissolving 1 gram ofminocycline (Mincycline HCl, USP, Chemos, GmbH) in a sodium hydroxide(0.1 gram) in methanol (10 milliliter) solution, then adding 2 grams ofrifampin (USP, Spectrum Chemical Mfr. Corp.) and butyl acetate (56.7milliliter). The solution was sonicated at 40° C. for 45 minutes thenallowed to cool to room temperature. At room temperature the siliconewas submerged fully and agitated in solution for 1 hour. After one hourthe silicone was removed, rinsed twice with methanol, blot dried andallowed to dry overnight. Following drug loading the anti-infectivearticles were sterilized by ethylene oxide (ETO) (exposure time ˜75 min:130 g of gas used [800-900 mg/L], relative humidity ˜65% at 65 kPa/50°C.), except for thick boots (see FIG. 9), which were e-beam sterilized(Acsion: Calibrated at 20° C., using FWT dosimeters that are heataged—on a single doe measurement the maximum uncertainty is estimated tobe ±6% at a 95% confidence level—Specified dose: 20-31.6 kGy Actualdose: 22.2-31.6 kGy).

C. Extraction and Drug Loading Analysis

Minocycline and rifampin were extracted from the ETO sterilized bootsand discs and subjected to HPLC analysis to determine the amount of drugloaded, generally as follows:

1. Extraction from Boot

Each boot was cut into pieces (24) with scissors so that they were smallenough to be submerged in the extraction volume (10-20 milliliters ofsolvent/gram of polymer). The pieces were extracted together in a 60-125milliliter jar w/top. All the pieces were placed in a jar, and 4:1THF/ethanol (50 milliliters for thick boots; 15 milliliters for thinboots) was added. The pieces were allowed to swell, and the drug wasextracted for 1 hour (1^(st) extraction). The extract was then collectedand transferred to a 25-100 milliliters volumetric flask. A second 4:1THF/ethanol (50 milliliters for thick boots w/holes; 10 milliliters forthin boots with holes) extraction was added to the jar, and the transferpipette was rinsed with this second extract and discarded. The pieceswere allowed to swell, and the drug was extracted for 1 hour (2^(nd)extraction). The extract was then collected and transferred to the25-100 milliliters volumetric flask containing the first extract. Asmall amount of extra solvent was needed to make up to volume due tosolvent lost to evaporation and polymer swell. This amount also servedas a final rinse of both the polymer and the transfer pipette.

2. Extraction from Discs

Desired sized discs (1-1 5/16″) were cut from the drug loaded sheetstock with a die press. The discs were sterilized with ETO (as above)and placed in a ounce jar w/ top, and 4:1 THF/ethanol (5 mL) was added.The disc was submerged fully in the 4:1 THF/ethanol system. The solutionwas stirred slowly on an orbital shaker. The disc was allowed to swell,and the drug was extracted from 1 hour (1^(st) extraction). The extractwas then collected and transferred to a 10 milliliter volumetric flask.A second 4:1 THF/ethanol (5 milliliters) extraction was added to thejar, and the transfer pipette was rinsed with this second extract anddiscarded. The resultant solution was slowly stirred on an orbitalshaker. The disc was allowed to swell, and the drug was extracted for 1hour (2^(nd) extraction). The extract was then collected and transferredto the 10mL volumetric flask containing the first extract. A smallamount of extra solvent was needed to make up to 10 mL due to solventlost to evaporation and polymer swell. This amount also served as afinal rinse of both the polymer and the transfer pipette.

3. HPLC Sample Preparation for Extraction Content Analysis

An aliquot of the solution in the volumetric flask was transferred to aHPLC vial (no additional dilution was required). THF/ethanol/drugextracts were added to the 1.5 milliliter HPLC vial. The HPLC vial wasplace in a refrigerated auto sampler (4° C.) and run, generally asfollows.

4. HPLC Method

Chromatographic conditions were as follows. Instrument (Agilent 1100stack); Column (Prodigy analytical column—150×4.6 mm); Detection mode(UV detection at 238 nm); Flow rate (1.0 mL/min); Column temperature(25° C.); Injection volume (10 uL); Mobile phase A (1.4 g/L dibasicsodium phosphate buffer pH 6.8); Mobile phase B (ACN 100%); andGradient:

Time (min). % B 0 12 10 36 25 75

The run time was 25 minutes, and the post time was 5 minutes.

Minocycline, rifampin and all known impurities have good solubility inmethanol and THF/ethanol 4:1.

D. Drug Elution

ETO sterilized drug loaded discs (thick and thin) were implantedsubcutaneously in the back of New Zealand white rabbits (albino rabbits,Oryctolagus cuniculus, white strain). The discs were removed from therabbits at 1, 3, 7 and 14 days. The drug contents of the explanted discswere compared to the contents of the discs at the start of theexperiment. An elution profile was generated based on the difference.

In addition, in-vitro drug elution studies were performed on 0.005″,0.010″ and 0.015″ thick drug loaded Dow Corning Silicone 4850 discs. Amonobasic sodium phosphate buffer (1.2 g/mL) solution at pH-6 was usedas the elution media. The silicone test articles are submerged in thesolution (20-40 mL solution/gram polymer) in small jars (typically 1oz.) with nylon mesh screens to keep the test articles from floating tothe surface. The jars are placed in an oscillating water bath at 37° C.to mimic physiological conditions. The media is replaced and assayed byHPLC periodically, to determine drug content eluted.

E. Additional In-Vivo Studies

Rifampin and minocycline loaded boots and discs were sterilized byethylene oxide (exposure time ˜75 min: 130 g of gas used [800-900 mg/L],relative humidity ˜65% at 65 kPa/50° C.). The sterilized boots wereplaced about Restore® implantable neurostimulators and the sterilizeddiscs were sutured to the connector block of the neurostimulators. Theneurostimualtors and associated anti-infective article (neurostimulatorsalone served as control) were implanted in a pocket formed in the backof New Zealand white rabbits (albino rabbits, Oryctolagus cuniculus,white strain) with or without lead extensions (Two lead extensions,model 37082, Medtronic, Inc.). An inoculum of Staphylococcus aureus(original primary source was ATCC 29213—tested culture obtained from aninfected pocket in a previous study) was introduced into thesubcutaneous pocket.

Briefly, a 2.0-2.5 cm lateral incision along the ventral surface of thespine was created through the dermal layer. A single incision was madeparallel to the mid-line of the back, cutting through the fascia andexposing the para vertebral muscle. The fascia membrane and portion ofthe trapezius muscle was incised with a scalpel creating a nominalimplant site. Bleeding was controlled with gauze and pressure. Usingblunt dissection, an implant pocket was created along the left lateralwall toward the lateral aspect of the left scapula of the rabbit. Thepocket extended approximately 3-4 cm toward the hamate process. Once thepocket was created, a sterile INS device with or without cover wasinserted into the pocket. A bacterial injection cannula was created byremoving the distal needle from a Vacutainer® blood collection set(Becton, Dickinson and Company). The 1.5 mm tube was placed into thepocket between the INS device and the infraspinous fossa of the scapula.The tube was temporarily secured with a purse-string suture. The deeperfacial layer of the mid-line skin incision was closed with absorbablesutures. The pocket was closed using a mattress stitch and 3.0 prolenesutures reconnecting the subcutaneous tissues. The cutaneous tissues wasthen closed using 3.0 prolene sutures and interrupted stitches leavingonly the distal end of the cannula in the pocket. A syringe was used toinject 5×10³ colony forming units (CFU) of S. aureus into the pocketusing the cannula followed by 1.0 mL of sterile saline from a separatesterile syringe. The cannula was removed and the purse-string suture wasclosed to seal the pocket. Animals were observed daily over the courseof 7 days. Surgical wounds associated with the implant were sutured. Theneurostimulators were explanted seven days following implantation. Therabbits and neurostimulators were then checked for the presence of aninfection. Animals will be observed daily over the course of 7 dayslooking for signs of illness, injury, or abnormal behavior. Attermination blood was drawn for bacterial culture. The INS/extension anddepleted cover were removed from the pocket. The cover was removed fromthe INS. The extensions were removed from the INS. The cover, INS, andextensions were agitated separately to remove adhered and nonadheredbacteria, this liquid was then cultured. The pocket was swabbed andcultured. If any of these five bacteria checks (blood, pocket, cover,INS, extensions) were positive then this was determined to be a positiveanimal

Seven rabbits received an INS in a thin boot with side holes and noextension, five received an INS in a thin boot with side holes andextension, seven received an INS in a thick boot with side hole and noextensions, twenty (ten each, in two different studies) received an INSin a thick boot and no extensions, seven received an INS with a thindisc with no extensions, five received an INS with a thin disc withextensions, and seven received an INS with a thick disc with noextensions. In all, 32 control animals received an INS alone (fourstudies using 5, 7, 10, and 10 control animals).

Drug loading and elution (7 day) analysis were performed as describedabove.

II. Results and Discussion

A. Drug Elution

The rates of elution (shown as percentages) of minocycline and rifampinfrom thin discs implanted in rabbits are shown in FIGS. 5 and 6,respectively. It is expected that thin boots should have similar elutionprofiles, assuming sink conditions when implanted. As can be seen,substantially all the minocycline and about 85% of the rifampin wereeluted within 24 hours. Within three days, essentially all the rifampinwas eluted. Surprisingly, discs with such rapid elution profiles wereable to effectively prevent infection formation (see FIG. 9).

The in vitro rates of elution (shown as percentages) of minocycline andrifampin from thin discs are shown in FIGS. 7 and 8. The elutionprofiles of 0.005″ thick discs were similar in vivo to in vitro.However, it is worth noting that the in vitro studies allow for adetermination of how much drug was actually eluted, while the in vivostudies allow for a determination of how much drug remained. As such,the results in vitro do not show 100% elution presumably because some ofthe drug degrades during test conditions, and thus released drug is notdetected. Regardless, as can be seen from FIGS. 7 and 8, substantiallyall the minocycline was eluted from the thin discs within a day, andsubstantially all the minocycline was eluted from the thin discs withtwo days.

As can be seen in FIGS. 7 and 8, it took considerably longer for a highpercentage of the drugs to elute from the 0.01″ and 0.015″thicknessdiscs than from the thin discs. It should be noted that the percentageof drug eluted from the thick discs was considerably lower (less than60%) than that of thin discs (greater than 90%). It is believed thatthis is due to increased degradation of drug in the thick discs as timepasses. That is, because it takes longer for drug to elute from thethick discs, there is more time for the drug to degrade before itelutes. Accordingly, it is believed that more degradants are eluted fromthicker discs. Exposing patients to increased levels of degradants mayprove undesirable.

The elution profile of the 0.01″ discs may serve to provide an elutionprofile that could be clinically very efficacious. As shown in FIGS. 7and 8, greater than 90% of minocycline eluted from the discs in a week,with about 70% eluting in a day, and nearly 80% of the rifampin elutedin a week, with more than 40% eluting in two-days. It has also beenfound that e-beam sterilized 0.01″ thickness boots with two side holescan elute at least 200 micrograms of rifampin between 4.5 and 5.5 days(3 to 4 days for ETO sterilized boots) after elution testing begins (notshown). Further ETO sterilized 0.01″ boots with two side holes can elutegreater than 167 micrograms of minocycline and greater than 200micrograms of rifampin in the time period between two and three days(not shown).

As discussed in more detail below and as shown in FIG. 9, thin discscontaining as little as 168 micrograms of minocycline and 193 microgramsof rifampin were effective at preventing infection. Accordingly, theability of 0.01″ thick silicone material to elute minocycline orrifampin at such levels at two to three or 4.5 to 5.5 days, may prove toprovide a very effective clinical outcome with little adverse effects.

B. Additional In-Vivo Studies

The amounts of minocycline and rifampin loaded can be seen the tablepresented in FIG. 9. As can be seen, amounts of minocycline as low as168 micrograms and rifampin as low as 193 micrograms were effective atpreventing infection (Thin Disc). In seven out of seven rabbitsimplanted without extensions and five out of five rabbits implanted withextensions, infection was prevented by discs loaded with between 168-190micrograms of minocycline and 193-203 micrograms of rifampin. It wasalso surprising that minoycline in the range of 778-869 micrograms andrifampin in the range of 832-998 micrograms (Thin Boot—2 Holes) waseffective in prevent infection in seven out of seven rabbits implantedwithout extensions and five out of five rabbits implanted withextensions. In each of the above-studies, all control animals (INS only,no disc or boot) had developed an infection in the surgical pocket(twelve out of twelve). It should be noted that the virulence of theinfection appears more severe in control rabbits receiving theextensions in addition to the INS. Thus, the efficacy of such low dosesof anti-infective agent in animals implanted with both INS andextensions is notable.

As discussed above with regard to the drug elution studies, it was alsosurprising that boots and discs that elute a substantial portion oftheir anti-infective agent within one day and that elute essentially allof their anti-infective agent within three days were effective atpreventing infection in the rabbits.

The surface area of the discs (1.23 square inches) was about 11% that ofthe surface area of the neurostimulator (13 square inches), yet evenwith the thin discs having relatively low drug loaded no infection wasobserved with the use of such discs (see, FIG. 9—Thin Disc).

While not tested, a thin (0.005 inches) boot having no side holes wouldbe expected to be able to be loaded with about three times the amount ofminocycline or rifampin as the thin boot with two holes, because thethick boot with no holes was loaded with about three times the amount ofminocycline and rifampin as the thick boot with two side holes.

C. Additional Discussion

While ETO sterilization was used in many of the studies describedherein, e-beam sterilization may result in anti-infective articles fromwhich more minocycline and rifampin may elute (relative to ETOsterilization). See, e.g., U.S. patent application Ser. No. 11/535,762,entitled “STERILIZED MINOCYCLINE AND RIFAMPIN-CONTAINING MEDICALDEVICE”, filed Sep. 27, 2006, which patent application is herebyincorporated herein by reference in its entirety to the extent that itdoes not conflict with the disclosure presented herein.

The minimum inhibitory concentration (MIC) of rifampin against thestrain of S. aureus used in the studies discussed above was determinedto be 0.06 micrograms/milliliter. Accordingly, one of skill in the artcan readily apply the teachings herein to other anti-infective agents todetermine an effective amount of the anti-infective agent, once the MICof the anti-infective agent is determined. For example, if the MIC ofthe anti-infective agent is similar to that of rifampin, then similaramounts of the anti-infective agent may be used. If the MIC of theanti-infective agent is ten times higher than the MIC for rifampin, tentimes more of the anti-infective agent may result in an effective amountof the anti-infective agent.

In further embodiments, normal needle function for the drug pump septumor port may be desired even if the disc covers the pump septum or portaccess. Piercability of the article 15 may allow for the article to beplaced in non-ideal locations on the implantable device 50 withoutreducing the operation and effectiveness of the implantable device 50.In other situations, the article 15 may be pierced if the article 15 isaccidentally released from the device. The adhesive that bonds orotherwise adheres the article 15 to the implantable device 50 may alsobe piercable as well, preferably without significantly impacting theeffectiveness of the adhesive.

In further embodiments a two or more year shelf live may be desired suchthat the article 15 is still effective for the intended purpose. Infurther embodiments less than two year shelf life may be required.Simulations of the shelf life may require exposing the test samples tovarious temperature and humidity conditions. The conditions may include−30° F. at ambient humidity, 95° F. at 85% humidity and 135° F. at 25%relative humidity (±5% tolerance). Samples may be held for 48 hours ateach temperature and be allowed to sit at ambient room temperature forat least 15 minutes between each cycle.

In further embodiments it may be necessary for the article 15 to stickto a dry, clean titanium and parylene surface. Such ability to stick tothe titanium or parylene surface may need to continue after exposure toother materials, such as, for example, blood, saline, sulfone, urethane,and siloxane. Further desirable characteristics may include a minimum180° peel strength of 0.5 foot pounds and maximum peel strength of 2.0foot pounds. In further embodiments the article 15 may be required toretain its adhering properties after being soaked in a liquid. One testfor adhesion may be to soak the article in a 0.85% to 0.90% salinesolution at 37° C.±5° C. for a minimum of 24 hours. In addition, thearticle 15 should retain its adhesion after such exposure. In furtherembodiments it may be desirable for cohesion to be greater thanadhesion.

In addition, the article 15 may preferably remain efficacious whenbacteria is captured between the implantable device 50 and the adhesive.In other words, the adhesive or other material used to adhere thearticle 15 to the implantable device 50 should not interfere with theoperation of the device. In some embodiments the article 15 may includeperforations through the article 15 and/or the adhesive to allow theanti-infective agent to achieve a greater spread of the anti-infectiveagent. In further embodiments, spraying both sides of the article 15with the agent (if spraying is used), loading the adhesive with theagent, or choosing an adhesive through which the agent will diffuse mayalso effectuate exposure of the area between the article 15 and theimplantable device 50.

In further embodiments it may be desirable for the anti-effective agentto be release from the article 15 for a minimum of 3 days. In stillfurther embodiments it may be desirable for the article 15 to stick tothe implantable device 50 for a minimum of 24 hours.

In further embodiments it may be desirable that any parlyene coatedsurface covered by the article 15 have the same electrical insulationproperties as a pristine parlyene coated area that was not covered bythe disc. Damaged parylene or inconsistent electrical insulationproperties may allow current leakage from the implantable device 50 andmay produce pocket stimulation.

In further embodiments a disc applicator may also be considered to avoidadhesive sticky residue on the gloves of the physician.

The adhesive is preferably thick enough on the polymer disc to beeffective, but no thicker. Over all thickness of the article 15 is aconcern for customer comfort and to limit mechanical interaction of thearticle 15 in. the implant environment, but at the same time the article15 needs to adhere to the implantable device 50 effectively. Therefore,the adhesive may have coverage to the outer diameter of the adherentside of the article 15 so that an un-adhered edge can not be “lifted” or“grabbed” during handling or in the pocket so as to facilitatedislodgement. In some embodiments it may be preferred that the adhesivemaintain coverage, conformity, and adherence to disc after disc isfolded 180 degrees on the non-adhesive side over a mandrel with a 0.010inch radius.

In still further embodiments the disc device diameter may beapproximately 0.75±0.01 in. In addition, the article 15 may be a varietyof sizes to as to be effective with a number of different medicaldevices 15. In still further embodiments, the article 15 and adhesivecomponent may be less that 0.07 in. thick.

In a further embodiment, certain rates of release of the anti-infectiveagent may be desired. In one example, using minocycline and rifampin,the article 15 may be structured such that the following release ratesare achieved.

Time Minocycline delivered Rifampin delivered 3 hours 500 ug 250 ug 8hours 750 ug 375 ug 24 hours  1300 ug  650 ug

In one embodiment, greater than 80% minocycline elution in 72 hours maybe desired. In further embodiments, total elution may be desired over aperiod of around seven days. In still further embodiments, longer orshorter elution times may be desired depending on the anti-effectiveagent(s) used, the type of implantable device 50, and other factors.Such elution rates may be a bolus rate or otherwise. As may beappreciated, killing the bacteria before it can replicate or can attachitself to the device and form a biofilm during the period immediatelyafter implant may result in the most effective treatment. Moreover,sustained release of low quantities of drug may be a concern forincreased bacterial resistance.

In further embodiments it may be desirable that the anti-infective agentor agents are not transferable or is not easily transferable to thegloves of the implantation physician or other medical professional thathandles the article 15. In those situations where an applicator is usedtransferal of the anti-infective agent may not be an issue. Where anapplicator is not used it may be desirable to formulate the article 15from materials to minimize drug transfer.

Further drug release parameters may include a variety of rangesdepending on the size and drug loading capability of the disc, such as,for example:

Time Minocycline delivered Rifampin delivered 3 hours 500-2,400 ug250-4,200 ug 8 hours 750-3,600 ug 375-6,250 ug 24 hours  1300-6,200 ug 650-10,800 ug 

As may be appreciated, the doses may be varied depending on the generaland local toxicity of the drugs, the drug transport in the pocket, thedispersion rate and the rate of uptake by the body, and the amount ofdrug that can be released from the surface area and volume of the disc.Such ranges may or may not be warranted depending on the efficacy andsafety of the drug.

Thus, embodiments of the REDUCTION OF INFECTION ASSOCIATED WITH MEDICALDEVICE are disclosed. One skilled in the art will appreciate that thepresent invention can be practiced with embodiments other than thosedisclosed. The disclosed embodiments are presented for purposes ofillustration and not limitation.

1. An implantable medical system comprising: an implantable medicaldevice having an exterior surface area; and an article configured tocontact the device and including (i) minocycline in an amount of between1 and 500 micrograms per square inch of the exterior surface area of thedevice and (ii) rifampin in an amount between 1 and 500 micrograms persquare inch of the exterior surface area of the device.
 2. The system ofclaim 1, wherein minocycline is present in the article in an amountbetween 1 and 100 micrograms per square inch of the exterior surfacearea of the device and wherein rifampin is present in the article in anamount between 1 and 100 micrograms per square inch of the exteriorsurface area of the device.
 3. The system of claim 1, whereinminocycline is present in the article in an amount between 3 and 50micrograms per square inch of the exterior surface area of the deviceand wherein rifampin is present in the article in an amount between 3and 50 micrograms per square inch of the exterior surface area of thedevice.
 4. The system of claim 1, wherein minocycline is present in thearticle in an amount between 5 and 25 micrograms per square inch of theexterior surface area of the device and wherein rifampin is present inthe article in an amount between 5 and 25 micrograms per square inch ofthe exterior surface area of the device.
 5. The system of claim 1wherein the article is bioabsorbable.
 6. The system of claim 1, whereinthe article has an average thickness of 0.01 inches or less
 7. Thesystem of claim 1, wherein the article has an average thickness of0.0075 inches or less.
 8. The system of claim 1, wherein the article hasan average thickness of 0.005 inches or less.
 9. The system of claim 1,wherein the article has first and second opposing major surfaces, thefirst major surface being in contact with the device and the secondmajor surface having a surface area of 30% or less than the exteriorsurface area of the device.
 10. An implantable medical systemcomprising: an implantable medical device having an exterior surfacearea; and an article configured to contact the exterior surface of thedevice, the article (i) having an average thickness 0.01 inches or lessand (ii) including an effective amount of minocycline and rifampin. 11.The system of claim 10, wherein the article has an average thickness of0.0075 inches or less.
 12. The system of claim 10, wherein the articlehas an average thickness of 0.005 inches or less.
 13. The system ofclaim 10, wherein the minocycline is present in the article in an amountof between 1 and 1500 micrograms per square inch of the exterior surfacearea of the device and wherein rifampin is present in the device in anamount of between 1 and 1500 micrograms per square inch of the exteriorsurface area of the device.
 14. The system of claim 10, wherein theminocycline is present in the article in an amount of between 3 and 750micrograms per square inch of the exterior surface area of the deviceand wherein rifampin is present in the device in an amount of between 3and 750 micrograms per square inch of the exterior surface area of thedevice.
 15. The system of claim 10, wherein the minocycline is presentin the article in an amount of between 5 and 400 micrograms per squareinch of the exterior surface area of the device and wherein rifampin ispresent in the device in an amount of between 5 and 400 micrograms persquare inch of the exterior surface area of the device.
 16. The systemof claim 10 wherein the article is bioabsorbable
 17. An implantablemedical system comprising: an implantable medical device having anexterior surface area; and an article configured to contact the exteriorsurface of the device, wherein the article includes an effective amountof minocycline and rifampin, and wherein the article is configured toelute 40% or more of the minocycline and rifampin within 48 hours ofbeing implanted in a patient.
 18. The system of claim 17, wherein thearticle configured to elute 60% or more of the minocycline and rifampinwithin 24 hours of being implanted in a patient,
 19. The system of claim17, wherein the article is configured to release substantially all theminocycline within 24 hours of being implanted.
 20. The system of claim17, wherein the article is configured to release substantially all therifampin within 72 hours of being implanted.
 21. An implantable medicalsystem comprising: an implantable medical device having an exteriorsurface area; and an article having first and second opposing majorsurfaces, the first major surface configured to contact the exteriorsurface of the device and the second major surface having a surface areaof 30% or less than the exterior surface area of the device and beingconfigured to contact tissue of a patient when implanted, wherein thearticle includes an effective amount of minocycline and rifampin.
 22. Ananti-infective article comprising: minocycline in an amount of between100 and 2000 and (ii) rifampin in an amount between 1000 and 2000micrograms, wherein the article has an average thickness of 0.01 inchesor less.
 23. An article according to claim 22, wherein the article hasan average thickness of 0.0075 inches or less.
 24. An article accordingto claim 22, wherein the article has an average thickness of 0.005inches or less.
 25. An article according to claim 22 wherein the articleis bioabsorbable.
 26. An implantable medical system comprising: animplantable medical device; and the article of 22, wherein the articleis configured to be contacted with the device when the device isimplanted.